Cardiovascular diseases are a leading cause of death resulting in almost 40% of deaths annually in the United States. Inadequate human myocardial regeneration poses a significant public health problem. It is estimated that 13 million Americans have coronary artery disease, and more than half a million experience a myocardial infarction every year. Human cardiac tissue responds to injury, e.g. myocardial infarction, with scar formation. Because the human heart is incapable of adequate muscle regeneration, survivors of a myocardial infarction typically develop heart failure, arrhythmias, thrombosis, and other complications.
Adult human hearts do not regenerate after injury; instead, the defect is replaced by fibrotic tissue. Most evidence to date indicates that cardiomyocyte proliferation, the cellular basis of regeneration, is not a significant component of the mammalian response to acute injury. In contrast to adult cardiomyocytes, fetal cardiomyocytes do proliferate during development.
Heart disease results in the loss of cardiomyocytes. It has been a significant challenge to develop effective treatments for cardiac repair because adult mammalian cardiomyocytes are highly differentiated cells and have been believed to be unable to proliferate. Mammalian cardiomyocytes withdraw from the cell cycle soon after birth and have lowered levels of cyclin A (Yoshizumi, M., et. al. (1995). J Clin Invest 95, 2275-2280). The fact that primary cardiac tumors occur rarely supports the notion that adult cardiomyocytes are highly restricted in their ability to divide. Because of its lack of proliferative potential, the primary response of the mammalian heart to injury is scar formation, which prevents cardiac repair. Thus the loss of cardiomyocytes after damage caused by events such as myocardial infarction generally results in compensatory responses that are inadequate to restore function. Unreplaced loss of cardiomyocytes leads to heart failure, a significant health problem worldwide.
Current therapies are also limited in their effectiveness. In order to sufficiently repair cardiac injury, it is necessary to provide a source of new cardiomyocytes. Proliferation of differentiated endogenous cardiomyocytes can enhance the regenerative capacity of mammalian hearts.
Accordingly, there is a need in the art for methods of increasing and/or promoting proliferation of adult mammalian cardiomyocytes.